Fecal microbial transplant for the treatment of pediatric inflammatory bowel disease

Table 1 Rates of clinical response after fecal microbial transplant for recurrent Clostridium difficile infection by fecal microbial transplant method

FMT method	Resolution of symptoms	Studies/total patients analyzed
Upper gastrointestinal tract (Nasogastric/nasoduodenal/nasojejunal) tube	77%	7/187
Enema	86%	6/264
Colonoscopy	90%	11/257
Upper gastrointestinal tract + colonoscopy	100%	1/27

Adapted from Drekonja et al[17] 2015. FMT: Fecal microbial transplant.

Table 2 Published pediatric fecal microbial transplant studies for recurrent Clostridium difficile infection

Ref	AGE (yr)	n	FMT route	Response rate
Hourigan et al[22], 2015	6-17	8	Colonoscopy	100%
Kronman et al[55], 2015	6-17	10	NG	90%
Wang et al[58], 2015	1	1	NJ	100%
Kelly et al[10], 2014	6-16	5	Not specified	89% (whole series)
Pierog et al[56], 2014	1-21	6	Colonoscopy	100%
Russell et al[57], 2014	1-21	10	NG (2); Colonoscopy (8)	90%
Walia et al[59], 2014	1-2	2	Colonoscopy	100%
Rubin et al[60], 2013	6-8	2	NG (64); EGD (7); Gastrostomy (previously placed) (4)	50%
Kahn et al[44], 2012	1	1	Colonoscopy	100%

Adapted from Hourigan et al[61], 2016. NG: Nasogastric; NJ: Nasojejunal; EGD: Esophagogastroduodenoscopy; FMT: Fecal microbial transplant.

Table 3 Rates of resolution of recurrent Clostridium difficile infection using fresh vs frozen fecal microbial transplant

Ref.	Fresh, n	Frozen, n	Fresh FMT resolution rate	Frozen/prepared FMT resolution rate
Hamilton et al[28], 2012	12	21	19/21	11/12
			90.5%	91.6%
Petrof et al[29], 2013	1	2	N/A	100%
			100%	100%
Lee et al[27], 2016	87 (PP)	91 (PP)	74/87, 85.1% (PP)	76/91, 83.5% (PP)
	111 (mITT)	108 (mITT)	78/111, 70.3% (mITT)	81/108, 75.0% (mITT)

PP: Per-protocol (patients received ≤ 2 same-modality FMT treatments with no Clostridium difficile infection (CDI) antibiotics administered between treatments, and no systemic antibiotics administered throughout study period; mITT: Modified intention-to-treat protocol (randomized patients; (1) received ≥ 1 same-modality FMT treatment but required antibiotics for CDI between administrations; (2) received different modality FMT treatments and did not complete follow-up period; or (3) required systemic antibiotic therapy for other infections throughout study protocol).

Table 4 Published pediatric fecal microbial transplant case series for inflammatory bowel disease

Ref.	AGE (yr)	Diagnosis, n	FMT protocol	Clinical response criteria	Response rate (%)
Kunde et al[32], 2013	7-21	9, UC	Serial enemas for 5 d	Decrease in PUCAI by > 15 points after FMT	7/9 clinical response at 1 wk (78)
					6/9 maintained response at 4 wk (67)
Kellermayer et al[33], 2015	14-16	3, UC	Serial enemas and colonoscopy over 6-12 wk	PUCAI < 35	3/3 endoscopic remission at 2 wk (100)
					3/3 histologic remission at 2 wk (100)
					3/3 clinical response at 4 wk (100)
					3/3 withdrawal of all immunotherapy at 15 wk (100)
Suskind et al[34], 2015	12-19	9, CD	Single FMT	PCDAI < 10	7/9 clinical response at 2 wk (78)
			via NGT		5/9 maintained response at 6, and 12 wk (56)
Suskind et al[35], 2015	13-16	4, UC	Single FMT	PUCAI < 10	No clinical response (0)
			via NGT		No laboratory benefit

FMT: Fecal microbial transplant; PCDAI: Pediatric Crohn’s Disease Activity Index; NGT: Nasogastric tube.

Table 5 Study characteristics and outcomes of published adult cohort studies of fecal microbial transplant for inflammatory bowel disease

Ref.	Clinical outcome	Follow-up
Wang et al[62], 2014	Clinical remission (1/2: 1 mo, 3 mo);	3 mo
	Clinical response (2/2: 1 wk)
Kump et al[49], 2013	Clinical remission (0/6: 90 d);	3 mo
	Clinical response (6/6: 2 wk; 4/6: stool frequency increased: 30 d; 2/6 sustained improvement: 90 d);
	Total colectomy (1/6), total proctocolectomy (2/6)
Wei et al[63], 2015	Mayo score: decreased from 5.80 ± 1.87 to 1.50 ± 1.35 (P < 0.01)	1 mo
Angelberger et al[26], 2013	Clinical remission (0/5: 12 wk);	3 mo
	Clinical response (1/5: 12 wk);
	Further deterioration (2/5: 4 wk)
Scaldaferri et al[64], 2015	Clinical remission (2/8: 2 wk; 2/8: 6 wk; 3/8: 12 wk);	3 mo
	Clinical response (2/8: 2 wk; 4/8: 6 wk; 4/8: 12 wk);
	Endoscopic response (2/6)
Ren et al[65], 2015	Mayo score: 11 patients achieved reduction of score	1-7 mo
Cui et al[50], 2015	Clinical improvement and steroid-free remission: 8/14;	3-18 mo
	Long-term remission: 4/14
Damman et al[66], 2015	Clinical remission (1/6: 4 wk; 0/6: 3 mo);	Not reported
	Worsening symptoms (6/6: 3 mo);
	Histology score improvement (5/6: 4 wk)
Borody et al[23], 2012	Complete clinical remission: 42/62;	3 mo
	Partial response: 15/62; Failure: 5/62;
	Normalization of mucosa: 8/21
Kump et al[49], 2013	Mayo score decrease > 3 points (5/9: 90 d);	1 mo
	Sustained mucosal healing: 1/9;
	Failure to sustain clinical improvement: 4/9
Landy et al[67], 2013	Clinical remission: 0/8;	1 mo
	Improvement in Cleveland Global Quality of Life score: 0/8

Adapted from Shi et al[48], 2016.

Table 6 Study characteristics and outcomes of published randomized controlled trials of fecal microbial transplant for inflammatory bowel disease

Group	Moayyedi et al (2015)	Rossen et al (2015)
n (active/placebo)	75 (38/37)	48 (23/25)
Population	Adult patients; Mild-moderate UC	Adult patients; Mild-moderate UC
Active arm	50 mL enema (8 g healthy donor stool)	500 mL nasoduodenal infusion (120 g healthy donor stool)
	Administered weekly × 6 wk	Administered at week 0, 3
Control arm	Normal saline	Autologous FMT (patient’s stool)
Inclusion of patients on Biologics	Yes, stable doses ≥ 12 wk	No
Primary outcome	Clinical remission (partial Mayo endoscopic score < 3 and Mayo endo score = 0) at week 7	Remission (SCCAI ≤ 2 + ≥ 1pt reduction in Mayo endoscopic score) at week 12
	Clinical response (reduction in full Mayo score ≥ 3)
Results	9/38 (24%) treated with FMT vs 2/37 (5%) controls (P = 0.03)	7/23 (30%) treated with FMT vs 5/25 (20%) controls (P = 0.51)

Adapted from Grinspan et al[40] 2015. SCCAI: Simplified Clinical Colitis Activity Index.

Table 7 Clinical trials of fecal microbial transplant for pediatric inflammatory bowel disease (registered through clinicaltrials.gov)

Location	Trial number	Diagnosis	Age (yr)	Donor	FMT route	Interven-tion	Protocol
Hamilton,	NCT02487238	UC	6-17	Anonymous	Enema	FMT, Saline	Retention enema; 2 × weekly × 6 wk; 33-wk follow up
Canada						Randomized Single Blinded
California, United States	NCT02291523	UC	7-2	Accepting volunteers	Colonoscopic	FMT, Saline	Patients on high-dose 5-ASA; 1 × colonoscopic administration; 12-mo follow up
						Randomized Double Blinded
Chongqing, China	NCT02335281	UC/CD	16-70	Not specified	Nasojejunal	FMT, Mesalazine	Single nasojejunal administration; 1-yr follow up
						Randomized Single Blinded
Texas, United States	NCT01947101	UC	12-20	Anonymous	Colonoscopic /Enema	FMT	Colonoscopic administration for first treatment; subsequent periodic treatments over 1-year with enema administration
Pennsylvania, United States	NCT02108821	UC/CD	2-22	Family member	Colonoscopic	Open Label	Fresh stool sample; 1 ×, 1-h duration; 6-mo follow up
						FMT
Michigan, United States	NCT01560819	UC/CD	7-21	Family member	Enema	Open Label	1-hour retention enema; daily × 5 d; 6-mo follow up
						FMT
Jerusalem, Israel;	NCT02033408	UC/CD	2-75	Not specified	Not specified	Open Label	Secondary treatment for antibiotic, corticosteroid failures; 3-yr follow up
Toronto, Canada;						FMT
Helsinki, Finland;						Open Label
Napoli, Italy;
Rome, Italy;
Krakow, Poland;
Malaga, Spain
Michigan, United States	NCT01560819	UC/CD	7-21	Family member/	Enema	FMT	Retention enema; Administered daily × 5 d; 6-mo follow up
				Chosen by family		Open Label
Turku, Finland	NCT01961492	UC	1-75	Anonymous	Colonoscopic	FMT	Single colonoscopic administration; 1-yr follow up
						Open Label
Jiangsu, China	NCT01793831	UC/CD	10-70	Not specified	Nasogastric	FMT	Single nasogastric administration; 12-mo follow up
Shaanxi, China						Open Label
Jiangsu, China	NCT01790061	UC	10-70	Not specified	Duodenal (gastroscopic)	FMT	1-mo follow up
Shaanxi, China						Open Label	Fresh, or frozen FMT administered via gastroscope
							No prior biologic, immunomodulatory, corticosteroid therapy
Jiangsu, China	NCT02560727	UC	10-70	Not specified	Colonoscopic	Not specified	12-mo follow up
							No prior biologic, immunomodulatory, corticosteroid therapy

UC: Ulcerative colitis; CD: Crohn’s disease.